Alpha1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha .sub.1 -adrenergic receptors are known to exist for which the genes have been cloned: alpha .sub.1A (previously known as alpha .sub.1C), alpha .sub.1B and alpha .sub.1D. The existence of an additional subtype, the alpha .sub.1L -adrenergic receptor subtype, has been proposed; however, the gene for the alpha .sub.1L -adrenergic receptor subtype has yet to be cloned.
Alpha1-adrenoceptor antagonists have been shown in numerous clinical studies to be effective in relieving the symptoms associated with benign prostatic hypertrophy (BPH). However, these compounds are all non-subtype-selective, and have the potential to cause significant side-effects, particularly cardiovascular effects such as postural hypotension, and CNS effects including aesthenia (tiredness). These effects can limit dosing, and thus clinical efficacy in reducing symptoms associated with BPH.
Pharmacological studies resulting in the subdivision of alpha.sub.1 -adrenoceptors into alpha.sub.1A -, alpha.sub.1B - and alpha.sub.1D -adrenoceptors have led to the suggestion that development of subtype-selective antagonists may allow improved symptomatic treatment of BPH/unstable bladder with a lower incidence of dose-limiting side-effects. An alpha.sub.1A -subtype-selective antagonist may, via a selective and significant decrease in outlet resistance, lead to improved pharmacotherapy for BPH. However, it must be noted that in BPH, it is often the irritative symptoms which prompt the patient to seek treatment, and that these irritative symptoms may be present even in patients with no demonstrable obstruction (i.e. normal urine flow rates). By combining both alpha.sub.1A - and alpha.sub.1B -subtype-selectivity in a drug molecule, a reduction of both obstructive and irritative symptoms in patients with BPH may be achieved. Lower levels or lack of alpha.sub.1D -adrenoceptor antagonism should lead to reduced or fewer side effects than those associated with the use of non-subtype-selective agents.
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